Myeloma is a malignant proliferation of plasma cells, which produce a monoclonal immunoglobulin (mc Ig). Myeloma is probably a multi-event disease, with the classical three step-development observed in cancer: initiation, promotion and progression. It is now established that all myeloma derive from a chronic state called Monoclonal Gammopathy of Undetermined Significance (MGUS). The risk of transformation of MGUS into myeloma is estimated at 1% per year per patient. Every year in Europe 20000 new cases of myeloma are diagnosed, and 3-5% of the UE population over 50 (close to 21 millions) present with MGUS. Yet numerous differences can be observed between myeloma and MGUS and healthy patients: variable isotype of monoclonal immunoglobulin (mc Ig), chronic infection, genetic lesions, and epigenetic changes.
Despite extensive biological and clinical research and numerous clinical trials, the etiopathology of MGUS and its evolution in myeloma remain largely unanswered questions. Different disease profiles may explain different disease evolutions and different treatment responses. Although numerous biological, clinical, therapeutic studies have been performed in the past decades yet the median survival in myeloma remains short (5 years), suggesting that new approaches to the MGUS and myeloma pathogenesis are still necessary.
Hence, it becomes urgent to find novel biomarkers useful to improve diagnosis and prognosis, and extend therapeutic options for this group of diseases. A promising approach is that MGUS and subsequently, myeloma result from antigen (Ag)-driven clonal proliferation, a pathogenic mechanism well established in other B-cell lineage malignancies but surprisingly neglected in myeloma and MGUS. Clonal myeloma plasma cells synthesize large amounts of Immunoglobulin (Ig) known as monoclonal immunoglobulin (mc Ig), but the role played by mc Ig production has not been investigated.
Patients with MGUS are currently not treated and not monitored for the risk of progression to myeloma. Heterogeneity of myeloma patients is acknowledged but the current efforts of patient stratification in regard of disease progression and response to treatment is limited to cytogenetic and genomic abnormalities, which are often secondary events in myeloma.
In current practice, mc Ig from patients diagnosed with myeloma or MGUS are assumed not to have functional antibody activity and their specificity is not studied.
Monoclonal gammopathy presenting patients are currently diagnosed by performing electrophoresis of patient plasma. However, those techniques remain insufficiently sensitive and do not take into account the specificity of mc Ig.
A previous study investigated the humoral immune status of patients with MGUS or myeloma in relation to common infectious agents (Karlsson et al. 2011 Clin Vaccine Immunol. 2011 June; 18(6):969-77. doi: 10.1128/CV1.00021-11). However, the determination of the humoral immune status of patients was done by testing serum samples, and the inventors have demonstrated that the reactivity of a serum sample is not indicative of the specificity of the mc Ig contained in the serum sample.
The inventors previously disclosed in a case report, the description of a patient suffering from plasma cell leukemia and having a mc Ig directed against the core protein of hepatitis C virus (HCV) (Hermouet S. et al., 2003 N Engl J Med; 348:178-179). Moreover, the inventors described 10 additional HCV-positive patients identified in a cohort of 700 patients presenting with a mc Ig. Mc Ig was purified for 7/10 patients and in 6/7 cases, the mc Ig was directed against HCV antigens and notably against HCV core protein and NS-4 protein (E. Bigot-Corbel E. et al., 2008 Blood. November 15; 112(10):4357-8).
No systematic study of the specificity of mc Ig has ever been done because screening mc Ig for a panel of Ag using classical assays such as ELISAs required purification of mc Ig and large quantities of purified mc Ig, usually not available. Other assays such as epitope reconstruction or epitope mediated antigen prediction (E-MAP) have proved disappointing because their technical complexity makes them difficult to use in clinical practice, and results obtained by these techniques need to be confirmed by other methods after purification of mc Ig.
In addition, these techniques are of indicative different value only and it is necessary to study the specificity of mc Ig with other assays.